Role of Neurotrophin Receptors in Neuroblastoma

神经营养蛋白受体在神经母细胞瘤中的作用

• 批准号: 6912614
• 负责人: DARRELL J YAMASHIRO
• 金额: $ 25.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6912614
• 关键词: Adenoviridae; angiogenesis; athymic mouse; autocrine; cell differentiation; fibroblasts; growth factor receptors; hypoxia; immunocytochemistry; metastasis; mitogen activated protein kinase; neoplastic growth; neuroblastoma; neurotrophic factors; oncoproteins; paracrine; transfection /expression vector; vascular endothelial growth factors

DESCRIPTION: (Adapted from the investigator's abstract) Neuroblastoma has a wide spectrum of clinical behavior, with tumors regressing spontaneously in infants, to widely metastatic disease and poor outcome despite intensive chemotherapy and bone marrow transplantation. The biological mechanism for these disparate clinical behaviors is likely to involve the neurotrophin receptors TrkA, TrkB, and TrkC, and their respective ligands, NGF, BDNF, and NT3. Favorable neuroblastomas express TrkA and TrkC, but not NGF or NT3. In contrast, unfavorable, metastatic neuroblastomas express TrkB and BDNF. Based on these observations we have proposed a model in which TrkA and TrkC promote favorable neuroblastoma by inducing neuronal d~(ferentiation, while an autocrine loop of TrkB and BDNF promotes unfavorable neuroblastoma by enhancing tumor growth, cell survival, and metastasis. In support of this model, studies have shown that TrkA and TrkC can induce neuronal differentiation, that TrkB can increase cell survival, stimulate cell invasiveness, and is chemoprotective. TrkB can also increase the expression of vascular endothelial growth factor (VEGF), suggesting that TrkB can induce angiogenesis, a critical step in tumor proliferation and metastases. The overall goal of this grant to obtain in vivo evidence for the Trk-NBL model. Our experiments will focus on TrkB and the autocrine/paracrine loop formed with BDNF, with the results compared with TrkC and NT3. For the in vivo studies we will use a xenograft model in the nude mouse that we have developed in our laboratory that produces large primary tumors and metastases to lung, liver, or bone marrow. Aim 1. We hypothesize that in vivo, TrkB promotes cell survival, proliferation, and metastases, while TrkC promotes differentiation. We will compare the ability of TrkB and TrkC to promote cell survival, tumor growth, metastases, differentiation, and protect against chemotherapy in vivo. Aim 2. We hypothesize that an autocrine or paracrine loop of BDNF/TrkB or NT3/TrkC promotes cell survival and differentiation. We will determine if autocrine expression of BDNF or NT3 in neuroblastoma cell lines or fibroblasts promotes differentiation or survival. Aim 3. We hypothesize that Trk receptors regulate angiogenesis in neuroblastoma. We will determine if TrkB and TrkC regulate the expression of VEGF and determine the signal pathways involved. We will determine if TrkB and TrkC protect neuroblastoma against hypoxia induced by anti-VEGF agents. By systematically comparing TrkB with TrkC in vivo, these studies will allow us to determine the validity of the Trk-NBL model.

描述：（改编自研究者摘要）神经母细胞瘤具有 广泛的临床行为，肿瘤自发消退， 婴儿，广泛转移性疾病和不良结局，尽管强化 化疗和骨髓移植。的生物学机制 这些不同的临床行为可能涉及神经营养因子 受体TrkA、TrkB和TrkC，以及它们各自的配体，NGF、BDNF，和 NT3。有利的神经母细胞瘤表达TrkA和TrkC，但不表达NGF或NT 3。在 相反，不利的转移性神经母细胞瘤表达TrkB和BDNF。基于 根据这些观察，我们提出了一个模型，其中TrkA和TrkC促进 通过诱导神经元分化， TrkB和BDNF的自分泌环通过增强神经母细胞瘤的生长促进不利的神经母细胞瘤 肿瘤生长、细胞存活和转移。为了支持这一模式，研究 已经表明TrkA和TrkC可以诱导神经元分化，TrkB 可以增加细胞存活，刺激细胞侵袭力， 化学保护TrkB还可增加血管内皮细胞的表达， 生长因子（VEGF），表明TrkB可以诱导血管生成，这是一个关键的 肿瘤增殖和转移步骤。这笔赠款的总体目标是 获得Trk-NBL模型的体内证据。我们的实验将集中在 TrkB和自分泌/旁分泌环与BDNF形成，结果 与TrkC和NT 3相比。对于体内研究，我们将使用异种移植物 在我们的实验室里开发的裸鼠模型， 大的原发性肿瘤和转移到肺、肝或骨髓。目标1。我们 假设在体内，TrkB促进细胞存活、增殖， 转移，而TrkC促进分化。我们将比较 TrkB和TrkC促进细胞存活、肿瘤生长、转移， 分化，并在体内保护免受化疗。目标二。我们 假设BDNF/TrkB或NT 3/TrkC自分泌或旁分泌环 促进细胞存活和分化。我们将确定是否自分泌 BDNF或NT 3在神经母细胞瘤细胞系或成纤维细胞中的表达促进 分化或生存。目标3。我们假设Trk受体调节 神经母细胞瘤中的血管生成。我们将确定TrkB和TrkC是否调节 VEGF的表达，并确定参与的信号通路。我们将 确定TrkB和TrkC是否保护神经母细胞瘤免受由 抗VEGF剂。通过系统地比较TrkB和TrkC在体内， 研究将使我们能够确定Trk-NBL模型的有效性。

项目成果

TNP-470 promotes initial vascular sprouting in xenograft tumors.

TNP-470 促进异种移植肿瘤中的初始血管萌芽。

• 发表时间: 2004
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Huang,Jianzhong;Frischer,JasonS;New,Tamara;Kim,EugeneS;Serur,Anna;Lee,Alice;Kadenhe-Chiwishe,Angela;Pollyea,DanielA;Yokoi,Akiko;Holash,Jocelyn;Yancopoulos,GeorgeD;Kandel,JessicaJ;Yamashiro,DarrellJ
• 通讯作者: Yamashiro,DarrellJ

Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma

• DOI: 10.3892/ijo_00000163
• 发表时间: 2009-02-01
• 期刊: INTERNATIONAL JOURNAL OF ONCOLOGY
• 影响因子: 5.2
• 作者: Zaghloul, Nibal;Hernandez, Sonia L.;Yamashiro, Darrell J.
• 通讯作者: Yamashiro, Darrell J.

Effects of potent VEGF blockade on experimental Wilms tumor and its persisting vasculature.

强效 VEGF 阻断对实验性肾母细胞瘤及其持续脉管系统的影响。

• 发表时间: 2004
• 期刊: International journal of oncology.
• 作者: Frischer,JasonS;Huang,Jianzhong;Serur,Anna;Kadenhe-Chiweshe,Angela;McCrudden,KimberlyW;O'Toole,Kathleen;Holash,Jocelyn;Yancopoulos,GeorgeD;Yamashiro,DarrellJ;Kandel,JessicaJ
• 通讯作者: Kandel,JessicaJ

Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade

• DOI: 10.3892/ijo_00000131
• 发表时间: 2009-01-01
• 期刊: INTERNATIONAL JOURNAL OF ONCOLOGY
• 影响因子: 5.2
• 作者: Huang, Jianzhong;Bae, Jae-O;Kandel, Jessica J.
• 通讯作者: Kandel, Jessica J.